DESCRIPTION, OVERALL (provided by applicant): This application serves as a competitive renewal of the Center of Excellence in Molecular Hematology that has been in existence at Children's Hospital Boston for the past ten years. The overall goal of the Center is to facilitate fundamental studies of the blood system in the two most tractable model organisms--the mouse and zebrafish. Focus on these systems takes advantage of the strengths of each organism, while also providing the benefits of synergy resulting from parallel developmental and genetic studies. During the past 5 years contributions from members of the Center have transformed our understanding of developmental hematopoiesis and offered new insights into how normal regulatory homeostasis is perturbed in disease. Yet current knowledge is incomplete. The foundation and achievements of the Center form the framework for our future efforts. We aim to define the molecular basis for genesis and function of blood stem cells, as well as the pathogenesis of disorders of the blood system. The Center is comprised of three core units. CORE A ->The Mouse Embryonic Stem Cell and Gene Targeting Core, provides resources for use and manipulation of mouse embryonic stem (ES) cells and the generation of gene modified mice. In addition, CORE A ->The Mouse Embryonic Stem Cell and Gene Targeting Core, provides advice, training, and support for members of the Center whose research requires mouse engineering. In the future, we will complement current gene targeting and transgenic methods with newer techniques, including formation of aggregation chimeras, nuclear transfer, and embryo freezing. CORE B ->The Zebrafish Core, is a zebrafish core that supports genetic and developmental studies of hematopoiesis. CORE B ->The Zebrafish Core, maintains numerous mutant zebrafish stocks, provides assistance to members of the Center in use of the zebrafish (including molecular markers,analysis, and design of mutant screens), and develops novel approaches (such as bone marrow transplantation) for exportation to other investigators. CORE C ->The Functional Genomics Core, a functional genomics and bioinformatics core, serves the Center and its members by providing genetic mapping resources for identification of mutant loci, analyzing gene expression patterns, and developing tools for generation of regulatory networks in hematopoiesis, both in the normal and mutant zebrafish in comparison with human gene expression patterns (eg in leukemias). Members of the Center include numerous hematology and related investigators in the immediate Harvard Medical School area, as well as mouse and zebrafish investigators located elsewhere in the US. The Center freely distributes reagents (mice and zebrafish) to academic investigators in order to support and stimulate research in the field.